Compounds for the modulation of MYC activity

ABSTRACT

The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application 62/385,610 filed on Sep. 9, 2016, which is incorporated herein by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 4, 2018, is named SYR-027_SL.txt and is 717 bytes in size.

BACKGROUND OF THE INVENTION

The transcription factor c-Myc plays an important role in the regulation of cell proliferation, cell growth, apoptosis, the cell cycle, and oncogenesis. c-Myc, a basic helix-loop-helix (bHLH) leucine zipper protein, is the most frequently occurring oncoprotein in a wide range of cancers, including breast, lung, and prostate cancers, where its deregulation provides growth factor-independent growth (Tansey, W. P. New J Sci (2014) 2014: 1-27; Dang, C. V. Cell (2012) 149:22-35). Myc proteins arise from three distinct gene families, c-myc, N-myc, and L-myc, each of which functions in an analogous manner but exhibits differences in expression levels and potency (Nesbit, C. E. et al, Oncogene (1999) 13:3004-3016; Tansey, W. P. New J Sci (2014) 2014:1-27; Dang, C. V. Cell (2012) 149:22-35). c-Myc requires heterodimerization with the small bHLH leucine zipper protein Max to bind DNA and activate gene transcription. Interaction of c-Myc with Max occurs at all c-Myc-bound genes in the genome and is essential for its oncogencity (Tansey, W. P. New J Sci (2014) 2014: 1-27). Further, Max is capable of dimerization with additional bHLH proteins that may influence the c-Myc-Max interaction, such as Mad and Mxl1 (Tansey, W. P. New J Sci (2014) 2014: 1-27; C. Grandori et al, Ann Rev Cell Dev Biol (2000) 16:653-699)

The myc gene is deregulated in cancer through multiple mechanisms including gene amplification, chromosomal translocation, deregulated upstream signaling, and protein stabilization, where the end result is increased levels of the resulting Myc protein (Nesbit, C. E. et al, Oncogene (1999) 13:3004-3016). Transgenic mouse models studies have demonstrated that genetic inactivation of myc leads to tumor regression in a range of cancer types (Jain, M. Science (2002) 297:102-104; Felsher, D. et al, Mol Cell (1999) 4:199-207; Choi, P. S. et al, Proc Natl Acad Sci USA (2011) 108:17432-17437; Murphy, D. et al. Cancer Cell (2008) 14:447-457; He, T. C. et al, Science (1998) 281:1509-1512). In some models, even brief inactivation of Myc significantly improves survival rates (Murphy, D. et al. Cancer Cell (2008) 14:447-457; Chesi, M. et al. Cancer Cell (2008) 13:167-180; Pelengaris, S. et al, Mol Cell (1999) 3:565-577). Additional studies have confirmed these findings in a number of other aggressive tumor models, where the prediction is that Myc inhibitors would have broad utility across multiple cancer types (Hermeking, H. Curr Cancer Drug Targets (2003) 3:163-175; Soucek, L. Nature (2008) 455:679-683; Konstantinopoulos, P. et al, JAMA (2011) 305:2349-2350; Soucek, L. et al, Nature (2008) 455:679-683). As such, there is a need to identify compounds that are capable of modulating Myc activity for use as therapeutic agents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A to 1H are a table of exemplary compounds of Formula I.

SUMMARY OF THE INVENTION

The present invention provides Myc inhibitors, for example c-Myc inhibitors, and in particular selective c-Myc inhibitors of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. The present invention further provides methods of using the compounds of the invention, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, to study the inhibition of c-Myc or other Myc family members (e.g., N-Myc or L-Myc), as well as the interaction of c-Myc with DNA or Max. The present invention still further provides methods of using the compounds of the invention, and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, as therapeutics for the prevention and/or treatment of diseases associated with overexpression and/or aberrant activity of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In certain embodiments, the inventive compounds are used for the prevention and/or treatment of proliferative diseases (e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases) in a subject.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives thereof, wherein Y, Z, R¹, R², R³, R⁴, m, n, p, and subvariables thereof are as defined herein.

In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein include a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof. The pharmaceutical composition may be useful for treating and/or preventing a proliferative or infectious disease.

In another aspect, the present invention provides methods of down-regulating the expression of c-Myc or other Myc family members (e.g., N-Myc or L-Myc) in a cell. In some embodiments, the method comprises contacting the cell with a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of inhibiting the activity of c-Myc or other Myc family members (e.g., N-Myc or L-Myc) in a cell. In some embodiments, the method comprises contacting the cell with a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of reducing Myc-regulated transcription of a gene in a cell (e.g. reducing transcription regulated by c-Myc, N-Myc, or L-Myc). In some embodiments, the method comprises contacting the cell with a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods for treating and/or preventing proliferative diseases. Exemplary proliferative diseases include cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases. In other embodiments, the present invention provides methods for treating and/or preventing an infectious disease (e.g., a viral infection).

In another aspect, the present invention provides methods for treating a proliferative disease (e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases) characterized by deregulated activity of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the deregulated activity of c-Myc or other Myc family members (e.g., N-Myc or L-Myc) comprises deregulation of upstream signaling, gene amplification, or chromosomal translocation by c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the proliferative disease is characterized by overexpression of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods for treating a proliferative disease (e.g., cancer (e.g., breast cancer, prostate cancer, lymphoma, or colorectal cancer), benign neoplasm, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) characterized by deregulation of other bHLH transcription factors, e.g., MITF, TWIST1, Max, E2A/TCF3, and HES1. In some embodiments, the proliferative disease is characterized by deregulation of the interaction between c-Myc and other bHLH transcription factors, e.g., Max. In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods for treating a subject determined to exhibit deregulated activity of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the deregulated Myc activity comprises overexpression of c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of reducing transcription of a gene upregulated in a proliferative disease (e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angiogenesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of treating a proliferative disease characterized by Myc addiction (e.g., addiction to c-Myc or other Myc family members, e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of inducing apoptosis of a cell in a biological sample or a subject. In some embodiments, the apoptosis is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of inducing terminal differentiation of a cell in a biological sample or subject. In some embodiments, the terminal differentiation is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of inducing senescence of a cell in a biological sample or subject. In some embodiments, the senescence is triggered by c-Myc or other Myc family members (e.g., N-Myc or L-Myc). In some embodiments, the method comprises administering to a subject a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, and optionally a pharmaceutically acceptable excipient, or compositions thereof.

In another aspect, the present invention provides methods of disrupting the interaction of one or more bHLH transcription factors, e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, with DNA in a cell. In some embodiments, a compound Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof may disrupt the interaction of one or more bHLH transcription factors, e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, with DNA in a cell.

In another aspect, the present invention provides methods of disrupting the activity of a complex of bHLH transcription factors, e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, in a cell. In some embodiments, a compound Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof may disrupt the activity of a complex of bHLH transcription factors, e.g., Myc (e.g., c-Myc or other Myc family members (e.g., N-Myc or L-Myc)), MITF, TWIST1, Max, E2A/TCF3, or HES1, in a cell.

In yet another aspect, the present invention provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment or prevention of an infectious disease in a subject. In certain embodiments, the infectious disease is a viral infection.

Another aspect of the present invention relates to kits comprising a container with a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits described herein further include instructions for administering the compound of Formula (I), or the pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or the pharmaceutical composition thereof.

The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Figures, the Examples, and the Claims.

Definitions

Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd) Edition, Cambridge University Press, Cambridge, 1987.

It is to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups and a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane that are likewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched.” “Optically-enriched,” as used herein, means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The term “aliphatic” or “aliphatic group”, as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-6 carbon atoms. In some embodiments, aliphatic groups contain 1-4 carbon atoms, and in yet other embodiments aliphatic groups contain 1-3 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (carbocyclyl)alkyl, (carbocyclyl)alkyl or (carbocyclyl)alkenyl.

The term “alkyl,” as used herein, refers to a monovalent saturated, straight- or branched-chain hydrocarbon such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the like.

The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. Exemplary alkenyl groups include, but are not limited to, —CH═CH₂ and —CH₂CH═CH₂.

The term “alkylene” refers to the diradical of an alkyl group.

The terms “halo” or “halogen” refer to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “haloalkyl” refers to a monovalent saturated straight or branched alkyl chain wherein at least one carbon atom in the chain is substituted with a halogen, e.g., F, Cl, Br, or I. In some embodiments, a haloalkyl group may comprise, e.g., 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ haloalkyl, C₁-C₁₀ haloalkyl, and C₁-C₆ haloalkyl. In certain instances, a haloalkyl group comprises 1, 2, 3, or 4 independently selected halogens substituted on 1, 2, 3, or 4 individual carbon atoms in the alkyl chain. In some embodiments, more than one halogen may be substituted on a single carbon atom. Representative haloalkyl groups include —CH₂F, —CF₃, CH₂CH(Cl)CH₃, and the like.

The term “heteroalkyl” refers to a monovalent saturated straight or branched alkyl chain wherein at least one carbon atom in the chain is replaced with a heteroatom, such as O, S, or N. In some embodiments, a heteroalkyl group may comprise, e.g., 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ heteroalkyl, C₁-C₁₀ heteroalkyl, and C₁-C₆ heteroalkyl. In certain instances, a heteroalkyl group comprises 1, 2, 3, or 4 independently selected heteroatoms in place of 1, 2, 3, or 4 individual carbon atoms in the alkyl chain. Representative heteroalkyl groups include —CH₂CH₂OCH₃, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)CH₃, and the like.

The term “heteroalkylene” refers to the diradical of a heteralkyl group.

The term “carbocyclic ring system”, as used herein, means a monocyclic, or fused, spiro-fused, and/or bridged bicyclic or polycyclic hydrocarbon ring system, wherein each ring is either completely saturated or contains one or more units of unsaturation, but where no ring is aromatic.

The term “carbocyclyl” refers to a radical of a carbocyclic ring system. Representative carbocyclyl groups include cycloalkyl groups (e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like).

The term “aromatic ring system” is art-recognized and refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein at least one ring is aromatic.

The term “aryl” refers to a radical of an aromatic ring system. Representative aryl groups include fully aromatic ring systems, such as phenyl, naphthyl, and anthracenyl, and ring systems where an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and the like.

The term “heteroaromatic ring system” is art-recognized and refers to monocyclic, bicyclic or polycyclic ring system wherein at least one ring is both aromatic and comprises a heteroatom; and wherein no other rings are heterocyclyl (as defined below). In certain instances, a ring which is aromatic and comprises a heteroatom contains 1, 2, 3, or 4 independently selected ring heteroatoms in such ring.

The term “heteroaryl” refers to a radical of a heteroaromatic ring system. Representative heteroaryl groups include ring systems where (I) each ring comprises a heteroatom and is aromatic, e.g., imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring is aromatic or carbocyclyl, at least one aromatic ring comprises a heteroatom and at least one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one, thiazolo-[4,5-c]-pyridinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, 5,6-dihydro-4H-thieno[2,3-c]pyrrolyl, 4,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and (iii) each ring is aromatic or carbocyclyl, and at least one aromatic ring shares a bridgehead heteroatom with another aromatic ring, e.g., 4H-quinolizinyl. In certain embodiments, the heteroaryl is a monocyclic or bicyclic ring, wherein each of said rings contains 5 or 6 ring atoms where 1, 2, 3, or 4 of said ring atoms are a heteroatom independently selected from N, O, and S.

The term “heterocyclic ring system” refers to monocyclic, or fused, spiro-fused, and/or bridged bicyclic and polycyclic ring systems where at least one ring is saturated or partially unsaturated (but not aromatic) and comprises a heteroatom. A heterocyclic ring system can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.

The term “heterocyclyl” refers to a radical of a heterocyclic ring system. Representative heterocyclyls include ring systems in which (i) every ring is non-aromatic and at least one ring comprises a heteroatom, e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (ii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is an aromatic carbon ring, e.g., 1,2,3,4-tetrahydroquinolinyl; and (iii) at least one ring is non-aromatic and comprises a heteroatom and at least one other ring is aromatic and comprises a heteroatom, e.g., 3,4-dihydro-1H-pyrano[4,3-c]pyridinyl, and 1,2,3,4-tetrahydro-2,6-naphthyridinyl. In certain embodiments, the heterocyclyl is a monocyclic or bicyclic ring, wherein each of said rings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring atoms are a heteroatom independently selected from N, O, and S.

“Partially unsaturated” refers to a group that includes at least one double or triple bond. A “partially unsaturated” ring system is further intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl groups) as herein defined. Likewise, “saturated” refers to a group that does not contain a double or triple bond, i.e., contains all single bonds.

As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable substituents for an optionally substituted alkyl, alkylene, haloalkyl, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl group and heteroaryl group include halogen, ═O, —CN, —OR^(c), —NR^(d)R^(e), —S(O)_(k)R^(c), —NR^(c)S(O)₂R^(c), —S(O)₂NR^(d)R^(e), —C(═O)OR^(c), —OC(═O)OR^(c), —OC(═O)R^(c), —OC(═S)OR^(c), —C(═S)OR^(c), —O(C═S)R^(c), —C(═O)NR^(d)R^(e), —NR^(c)C(═O)R^(c), —C(═S)NR^(d)R^(e), —NR^(c)C(═S)R^(c), —NR^(c)(C═O)OR^(c), —O(C═O)NR^(d)R^(e), —NR^(c)(C═S)OR^(c), —O(C═S)NR^(d)R^(e), —NR^(c)(C═O)NR^(d)R^(e), —NR^(c)(C═S)NR^(d)R^(e), —C(═S)R^(c), —C(═O)R^(c), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, carbocyclyl, (C₁-C₆-alkylene)-carbocyclyl, (C₁-C₆-heteroalkylene)-carbocyclyl, heterocyclyl, (C₁-C₆-alkylene)-heterocyclyl, (C₁-C₆-heteroalkylene)-heterocyclyl, aryl, (C₁-C₆-alkylene)-aryl, (C₁-C₆-heteroalkylene)-aryl, heteroaryl, (C₁-C₆-alkylene)-heteroaryl, or (C₁-C₆-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more of halogen, —OR^(c), —NO₂, —CN, —NR^(c)C(═O)R^(c), —NR^(d)R^(e), —S(O)_(k)R^(c), —C(═O)OR^(c), —C(═O)NR^(d)R^(e), —C(═O)R^(c), C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ heteroalkyl, and wherein R^(c) is hydrogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, carbocyclyl, (C₁-C₆-alkylene)-carbocyclyl, (C₁-C₆-heteroalkylene)-carbocyclyl, heterocyclyl, (C₁-C₆-alkylene)-heterocyclyl, (C₁-C₆-heteroalkylene)-heterocyclyl, aryl, (C₁-C₆-alkylene)-aryl, (C₁-C₆-heteroalkylene)-aryl, heteroaryl, (C₁-C₆-alkylene)-heteroaryl, or (C₁-C₆-heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halogen, hydroxy, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R^(d) and R^(e) are each independently selected from hydrogen, C₁-C₆ alkyl, or C₁-C₆ heteroalkyl; and k is 0, 1 or 2.

These and other exemplary substituents are described in more detail in the Detailed Description, Figures, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

The following definitions are more general terms used throughout the present application:

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of Formula (I) may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound which is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R.x H₂O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R.0.5 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R.2 H₂O) and hexahydrates (R.6 H₂O)).

A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) and/or other non-human animals, for example, mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys). In certain embodiments, the animal is a mammal. The animal may be a male or female and at any stage of development. A non-human animal may be a transgenic animal.

The terms “administer,” “administering,” or “administration,” as used herein refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an inventive compound, or a pharmaceutical composition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

As used herein, the terms “condition,” “disease,” and “disorder” are used interchangeably.

An “effective amount” of a compound of Formula (I) refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of Formula (I) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, in treating cancer, an effective amount of an inventive compound may reduce the tumor burden or stop the growth or spread of a tumor.

A “therapeutically effective amount” of a compound of Formula (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

A “prophylactically effective amount” of a compound of Formula (I) is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.

A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites.

As used herein, the term “cancer” refers to a malignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelio sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “angiogenesis” refers to the formation and the growth of new blood vessels. Normal angiogenesis occurs in the healthy body of a subject for healing wounds and for restoring blood flow to tissues after injury. The healthy body controls angiogenesis through a number of means, e.g., angiogenesis-stimulating growth factors and angiogenesis inhibitors. Many disease states, such as cancer, diabetic blindness, age-related macular degeneration, rheumatoid arthritis, and psoriasis, are characterized by abnormal (i.e., increased or excessive) angiogenesis. Abnormal angiogenesis refers to angiogenesis greater than that in a normal body, especially angiogenesis in an adult not related to normal angiogenesis (e.g., menstruation or wound healing). Abnormal angiogenesis can provide new blood vessels that feed diseased tissues and/or destroy normal tissues, and in the case of cancer, the new vessels can allow tumor cells to escape into the circulation and lodge in other organs (tumor metastases).

As used herein, an “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis.

As used herein, an “autoimmune disease” refers to a disease arising from an inappropriate immune response of the body of a subject against substances and tissues normally present in the body. In other words, the immune system mistakes some part of the body as a pathogen and attacks its own cells. This may be restricted to certain organs (e.g., in autoimmune thyroiditis) or involve a particular tissue in different places (e.g., Goodpasture's disease which may affect the basement membrane in both the lung and kidney). The treatment of autoimmune diseases is typically with immunosuppression, e.g., medications which decrease the immune response. Exemplary autoimmune diseases include, but are not limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus erythematosis, rheumatoid, arthritis, psoriatic arthritis, systemic lupus erythematosis, psoriasis, ulcerative colitis, systemic sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody syndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis (e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosing spondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto's thyroiditis, and cardiomyopathy.

The term “autoinflammatory disease” refers to a category of diseases that are similar but different from autoimmune diseases. Autoinflammatory and autoimmune diseases share common characteristics in that both groups of disorders result from the immune system attacking a subject's own tissues and result in increased inflammation. In autoinflammatory diseases, a subject's innate immune system causes inflammation for unknown reasons. The innate immune system reacts even though it has never encountered autoantibodies or antigens in the subject. Autoinflammatory disorders are characterized by intense episodes of inflammation that result in such symptoms as fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal buildup of a blood protein in vital organs. Autoinflammatory diseases include, but are not limited to, familial Mediterranean fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), deficiency of the interleukin-1 receptor antagonist (DIRA), and Behçet's disease.

The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. Biological samples also include those biological samples that are transgenic, such as transgenic oocyte, sperm cell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

Compounds

In one embodiment of the present invention, provided are compounds of Formula (I):

or a pharmaceutically acceptable salt solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

Y is selected from O, S and N(R³);

Z is selected from C(R⁴)(N(R⁵)(R⁶)) and N(R);

R¹ is selected from halo, -Q, —C₁-C₄ alkyl, —N(R³)—C(O)-Q, —N(R³)—C(O)—(C₁-C₄ alkyl), —N(R³)-Q, —N(R³)₂, —S-Q, —S—(C₁-C₄ alkyl), —C(O)-Q, —C(O)—(C₁-C₄ alkyl), —C(O)—N(R³)-Q, —C(O)—N(R³)₂, —O-Q, —O—(C₁-C₄ alkyl), —C(O)—O-Q and —C(O)—O—R³, wherein:

Q is selected from a carbocyclyl, heterocyclyl, aryl or heteroaryl, wherein Q is optionally substituted; and each alkyl in R¹ is optionally substituted;

R² is selected from —C(R^(2a))(R^(2b))(R^(2c)), carbocyclyl, aryl, heterocyclyl and heteroaryl, wherein any carbocyclyl, aryl, heterocyclyl and heteroaryl is optionally substituted, wherein:

R^(2a) is selected from hydrogen, halogen, CN, C₁-C₄ alkyl, and C₁-C₄ heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted;

each of R^(2b) and R^(2c) is independently selected from hydrogen, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)O(C₁-C₆ heteroalkyl), C(O)N(R^(3a))(R^(3b)), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl and (C₁-C₆ heteroalkylene)-heteroaryl,

wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R^(2b) and R^(2c) is optionally and independently substituted;

each R³ is independently selected from hydrogen, —C₁-C₆ alkyl, and —C₁-C₆ heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; or

two R³ bound to a common nitrogen atom are optionally taken together with the nitrogen atom to which they are commonly bound to form a 4-11 member heterocyclyl or heteroaryl;

each R⁴ is independently selected from hydrogen, halogen, —CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, N(R³)(R³), C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)N(R³)(R³), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, and (C₁-C₆ heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R⁴ is optionally and independently substituted;

R⁵ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, (C₁-C₆ heteroalkylene)-heteroaryl, CH₂C(O)OR⁸, CH₂C(O)N(R¹⁰)(R⁹), and CH₂CH₂N(R¹⁰)(R⁹), wherein:

R⁸ is selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, (C₀-C₃ alkylene)-carbocyclyl, and (C₀-C₃ alkylene)-heterocyclyl;

R⁹ is hydrogen or C₁-C₄ alkyl; and

R¹⁰ is selected from hydrogen, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, (C₀-C₄ alkylene)-carbocyclyl, (C₀-C₄ alkylene)-heterocyclyl, (C₀-C₄ alkylene)-aryl, (C₀-C₄ alkylene)-heteroaryl, (C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), (C₁-C₄ alkyl)-N—(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl), and C(O)—O—(C₁-C₄ alkyl), or

R¹⁰ and R⁹ are taken together with the nitrogen atom to which they are commonly bound to form a 4-11 membered heterocyclyl or heteroaryl;

each of R⁶ and R⁷ is independently selected from hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C(O)(C₁-C₆ alkyl), C(O)O(C₁-C₆ alkyl), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene) heteroaryl, and (C₁-C₆ heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of each of R⁵ and R⁶ is optionally and independently substituted; or

R⁶ and R⁷ are taken together with the nitrogen atom to which they are bound to form an optionally substituted heterocyclyl;

n is 0, 1 or 2;

m is 0, 1 or 2;

n+m=1, 2 or 3; and

p is 0, 1, 2, 3, 4, 5, or 6; and

wherein the compound is other than

In certain embodiments, Y is S.

In certain embodiments, Z is N(R⁵). In certain embodiments, Z is N(R⁵), and R⁵ is hydrogen.

In certain embodiments, Y is S and Z is N(R⁵). In certain embodiments, Y is S, Z is N(R⁵), and R⁵ is hydrogen.

In certain embodiments, R¹ is selected from halo, -Q, —N(R³)—C(O)—(C₁-C₄ alkyl), —N(R³)-Q, —N(R³)₂, —C(O)-Q, —C(O)—(C₁-C₄ alkyl), —C(O)—N(R³)-Q, —C(O)—N(R³)₂, —O-Q, —O—(C₁-C₄ alkyl), and —C(O)—O—R³.

In certain embodiments, R¹ is selected from halo, -Q, —N(R³)—C(O)—(C₁-C₄ alkyl), —C(O)—(C₁-C₄ alkyl), —C(O)—N(R³)-Q, —C(O)—N(R³)₂, and —C(O)—O—R³.

In certain embodiments, R¹ is selected from bromo, —NH—C(O)—CH₃, —C(O)N(CH₃)₂, —C(O)NH, —(CH₂)₂—OCH₃, —C(O)—OCH₃, —C(O)—NH—CH₂ CH₂(O)(CH₃), —C(O)—NH—CH(CH₃)₂, —C(O)OH, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, and morpholin-4-ylcarbonyl.

In certain embodiments, R¹ is halo. In certain embodiments, R¹ is -Q. In certain embodiments, R¹ is —N(R³)—C(O)—(C₁-C₄ alkyl). In certain embodiments, R¹ is —C(O)—(C₁-C₄ alkyl). In certain embodiments, R¹ is —C(O)—N(R³)-Q. In certain embodiments, R¹ is —C(O)—N(R³)₂. In certain embodiments, R¹ is —C(O)—O—R³.

In certain embodiments, Q is selected from heterocyclyl, aryl, and heteroaryl, each of which is optionally substituted. In certain embodiments, Q is a 6-membered ring. In certain embodiments, Q is selected from phenyl, oxygen-containing heterocyclyl, and a nitrogen-containing heterocyclyl or heteroaryl, each of which is optionally substituted. In certain embodiments, Q is a 6-membered nitrogen-containing ring. In certain embodiments, Q is pyridinyl, pyrimidinyl, pyridinonyl, or tetrahydropyridinyl, each of which is optionally substituted. In certain embodiments, Q is a 6-membered oxygen-containing ring. In some embodiments, Q is dihydropyranyl, which is optionally substituted.

In certain embodiments, Q is a 5-membered ring. In certain embodiments, Q is a nitrogen-containing 5-membered ring. In certain embodiments, Q is selected from imidazolyl or pyrazolyl, each of which is optionally substituted.

In certain embodiments, R² is —C(R^(2a))(R^(2b))(R^(2c)). In certain embodiments, R² is —C(R^(2a))(R^(2b))(R^(2c)), R^(2a) and R^(2b) are simultaneously hydrogen; and R^(2c) is selected from hydrogen, optionally substituted C₁-C₆ alkyl, and optionally substituted C₁-C₆ heteroalkyl.

In certain embodiments, R² is selected

from —CH₃, —(CH₂)₂—NH—CH(CH₃)₂, —(CH₂)₂—NH—(CH₂)₂—OCH₃,

and —(CH₂)₂—NH—CH(CH₃)—CH₂CH₃.

In certain embodiments, R² is —C(R^(2a))(R^(2b))(R^(2c)), wherein R^(2a) and R^(2b) are simultaneously hydrogen; and R^(2c) is selected from optionally substituted C₁-C₆ alkyl and optionally substituted C₁-C₆ heteroalkyl. In certain embodiments, R² is not CH₃.

In certain embodiments, R³ is hydrogen, C₁-C₆ alkyl, or C₁-C₆ heteroalkyl. In certain embodiments, R³ is hydrogen. In certain embodiments, R³ is hydrogen, methyl, isopropyl, CH₂CH₂OCH₃.

In certain embodiments, two R³ bound to a common nitrogen atom are optionally taken together with the nitrogen atom to which they are commonly bound to form a 4-11 member heterocyclyl or heteroaryl. In certain embodiments, two R³ are taken together with the nitrogen atom to which they are commonly bound to form a morphilinyl, piperidinyl, piperazinyl ring, each of which is optionally substituted.

In certain embodiments, p is 0. In certain embodiments, n is 1. In certain embodiments, m is 0. In certain embodiments, n is 1 and m is 1. In certain embodiments, p is 0, n is 1, and m is 1.

In certain embodiments, the compound of Formula (I) is selected from the group consisting of any one of the compounds in the tables in FIGS. 1A to 1H and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives thereof.

In certain embodiments, the compound of Formula (I) is selected from the group consisting of any one of the compounds in the table in FIGS. 1A to 1H and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and isotopically labeled derivatives thereof.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, as described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition of the invention comprises a compound Formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of Formula (I) (the “active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between about 0.1% and about 100% (w/w) active ingredient.

The term “pharmaceutically acceptable excipient” refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention are any of those that are well known in the art of pharmaceutical formulation and include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous and intradermal), by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions are administrable intravenously and/or orally.

The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitoneal intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a provided oral formulation is formulated for immediate release or sustained/delayed release. In some embodiments, the composition is suitable for buccal or sublingual administration, including tablets, lozenges and pastilles. A provided compound can also be in micro-encapsulated form.

Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions or in an ointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit form, e.g., single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

In certain embodiments, the compounds of Formula (I) may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

It will be also appreciated that a compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agents and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs). The inventive kits may be useful for preventing and/or treating a proliferative disease (e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease). The kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound. In some embodiments, the inventive pharmaceutical composition or compound provided in the container and the second container are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, and isotopically labeled derivative, or a pharmaceutical composition thereof. In certain embodiments, the kit of the invention includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits are useful in preventing and/or treating a proliferative disease in a subject. In certain embodiments, the kits further include instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically and labeled derivative thereof, or a pharmaceutical composition thereof, to a subject to prevent and/or treat a proliferative disease.

Methods of Treatment and Uses

The present invention also provides methods for the treatment or prevention of a proliferative disease (e.g., cancer, benign neoplasm, angiogenesis, inflammatory disease, autoinflammatory disease, or autoimmune disease) or an infectious disease (e.g., a viral disease) in a subject. Such methods comprise the step of administering to the subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods described herein include administering to a subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In certain embodiments, the subject being treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog, or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

The proliferative disease to be treated or prevented using the compounds of Formula (I) will typically be associated with deregulated activity of c-Myc. Deregulated activity of c-Myc may constitute an elevated and/or an inappropriate (e.g., abnormal) activity of c-Myc. In certain embodiments, c-Myc is not overexpressed, and the activity of c-Myc is elevated and/or inappropriate. In certain other embodiments, c-Myc is overexpressed, and the activity of c-Myc is elevated and/or inappropriate. The compounds Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may inhibit the activity of c-Myc and be useful in treating and/or preventing proliferative diseases.

In other embodiments, the proliferative disease to be treated or prevented using the compounds of Formula (I) may be associated with deregulated activity a Myc family member, e.g., N-Myc or L-Myc. Deregulated activity of a Myc family member (e.g., N-Myc or L-Myc) may constitute an elevated and/or an inappropriate (e.g., abnormal) activity of one or more Myc family members (e.g., N-Myc or L-Myc). In certain embodiments, a Myc family member (e.g., N-Myc or L-Myc) is not overexpressed, and the activity of said Myc family member (e.g., N-Myc or L-Myc) is elevated and/or inappropriate. In certain other embodiments, a Myc family member (e.g., N-Myc or L-Myc) is overexpressed, and the activity of said Myc family member (e.g., N-Myc or L-Myc) is elevated and/or inappropriate. The compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may inhibit the activity of a Myc family members (e.g., N-Myc or L-Myc) and be useful in treating and/or preventing proliferative diseases.

A proliferative disease may also be associated with inhibition of apoptosis of a cell in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being within the scope of the invention. Inhibition of the activity of c-Myc or other Myc family member (e.g., N-Myc or L-Myc) may cause cytotoxicity via induction of apoptosis. The compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, may induce apoptosis, and therefore, may be useful in treating and/or preventing proliferative diseases.

In certain embodiments, the proliferative disease to be treated or prevented using the compounds of Formula (I) is cancer. All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the proliferative disease is a cancer associated with dependence on BCL-2 anti-apoptotic proteins (e.g., MCL-1 and/or XIAP). In certain embodiments, the proliferative disease is a cancer associated with overexpression of Myc. In certain embodiments, the proliferative disease is a hematological malignancy. In certain embodiments, the proliferative disease is a blood cancer. In certain embodiments, the proliferative disease is leukemia. In certain embodiments, the proliferative disease is chronic lymphocytic leukemia (CLL). In certain embodiments, the proliferative disease is acute lymphoblastic leukemia (ALL). In certain embodiments, the proliferative disease is T-cell acute lymphoblastic leukemia (T-ALL). In certain embodiments, the proliferative disease is chronic myelogenous leukemia (CML). In certain embodiments, the proliferative disease is acute myelogenous leukemia (AML). In certain embodiments, the proliferative disease is lymphoma. In certain embodiments, the proliferative disease is melanoma. In certain embodiments, the proliferative disease is multiple myeloma. In certain embodiments, the proliferative disease is a bone cancer. In certain embodiments, the proliferative disease is osteosarcoma. In some embodiments, the proliferative disease is Ewing's sarcoma. In some embodiments, the proliferative disease is triple-negative breast cancer (TNBC). In some embodiments, the proliferative disease is a brain cancer. In some embodiments, the proliferative disease is neuroblastoma. In some embodiments, the proliferative disease is a lung cancer. In some embodiments, the proliferative disease is small cell lung cancer (SCLC). In some embodiments, the proliferative disease is large cell lung cancer. In some embodiments, the proliferative disease is a benign neoplasm. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the invention.

In some embodiments, the proliferative disease is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the invention.

In certain embodiments, the proliferative disease is an inflammatory disease. All types of inflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the invention. In certain embodiments, the inflammatory disease is rheumatoid arthritis. In some embodiments, the proliferative disease is an autoinflammatory disease. All types of autoinflammatory diseases disclosed herein or known in the art are contemplated as being within the scope of the invention. In some embodiments, the proliferative disease is an autoimmune disease. All types of autoimmune diseases disclosed herein or known in the art are contemplated as being within the scope of the invention.

The cell described herein may be an abnormal cell. The cell may be in vitro or in vivo. In certain embodiments, the cell is a proliferative cell. In certain embodiments, the cell is a blood cell. In certain embodiments, the cell is a lymphocyte. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a leukemia cell. In certain embodiments, the cell is a CLL cell. In certain embodiments, the cell is a melanoma cell. In certain embodiments, the cell is a multiple myeloma cell. In certain embodiments, the cell is a benign neoplastic cell. In certain embodiments, the cell is an endothelial cell. In certain embodiments, the cell is an immune cell.

In another aspect, the present invention provides methods of down-regulating the expression of c-Myc or other Myc family member (e.g., N-Myc or L-Myc) in a biological sample or subject. In certain embodiments, the present invention provides methods of down-regulating the expression of c-Myc in a biological sample or subject. In another aspect, the present invention provides methods of down-regulating the expression of other bHLH transcription factors, such as MITF, TWIST1, and Max, in a biological sample or subject.

In certain embodiments, the methods described herein comprise the additional step of administering one or more additional pharmaceutical agents in combination with the compounds of Formula (I) a pharmaceutically acceptable salt thereof, or compositions comprising such compound or pharmaceutically acceptable salt thereof. Such additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. The additional pharmaceutical agent(s) may synergistically augment inhibition of c-Myc or other Myc family member (e.g., N-Myc or L-Myc) induced by the inventive compounds or compositions of this invention in the biological sample or subject. In certain embodiments, the additional pharmaceutical agent is flavopiridol, triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887, BS-181, (S)—CR8, (R)—CR8, ABT-737, or NU6140. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a mitogen-activated protein kinase (MAPK). In certain embodiments, the additional pharmaceutical agent is an inhibitor of a Bcl-2 protein. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a glycogen synthase kinase 3 (GSK3). In certain embodiments, the additional pharmaceutical agent is an inhibitor of an AGC kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a CaM kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a casein kinase 1. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a STE kinase. In certain embodiments, the additional pharmaceutical agent is an inhibitor of a tyrosine kinase. Thus, the combination of the inventive compounds or compositions and the additional pharmaceutical agent(s) may be useful in treating proliferative diseases resistant to a treatment using the additional pharmaceutical agent(s) without the inventive compounds or compositions.

In yet another aspect, the present invention provides the compounds of compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof, for use in the treatment of a proliferative disease in a subject. In certain embodiments, provided by the invention are the compounds described herein, and pharmaceutically acceptable salts and compositions thereof, for use in the treatment of a proliferative disease in a subject. In certain embodiments, provided by the invention are the compounds described herein, and pharmaceutically acceptable salts and compositions thereof, for use in inhibiting cell growth. In certain embodiments, provided by the invention are the compounds described herein, and pharmaceutically acceptable salts and compositions thereof, for use in inducing apoptosis in a cell. In certain embodiments, provided by the invention are the compounds described herein, and pharmaceutically acceptable salts and compositions thereof, for use in inhibiting transcription.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

The compounds provided herein can be prepared from readily available starting materials using modifications to the specific synthesis protocols set forth below that would be well known to those of skill in the art. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in Greene et al., Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.

TABLE 1 Abbreviations Ac acetyl Ac₂O acetic anyhydride AcOH acetic acid ACN acetonitrile aq. aqueous atm atmospheres Boc tert-butoxy carbonyl Boc₂O di-t-butyl dicarbonate Bn benzyl DCM bichloromethane DIPEA N,N-diisopropyl ethylamine DMF dmethylformamide DMSO dimethylsulfoxide DPPA diphenoxyphosphoryl azide EDTA ethylenediamine tetraacetic acid eq(s). equivalent(s) EtOAc ethyl acetate Et ethyl EtOH ethanol Et₃N, TEA triethylamine g gram(s) h hour(s) Hex hexanes HOBt 1-Hydroxybenzotriazole HPLC high pressure liquid chromatography IPA isopropanol LCMS; LC-MS liquid chromatography mass spectrometry MeOH methanol mg milligram(s) MHz megahertz min minute(s) mL; ml milliliter(s) MS mass spectrometry NMe N-methyl NMR nuclear magnetic resonance Ph phenyl pyr pyridine r.t.; rt; RT room temperature S., sat. saturated T₃P propylphosphonic anydride TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography

Example 1. Synthesis of N-(3-(4-phenylthiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (Compound 100)

Step 1: 2-(4-phenylthiazol-2-yl)acetonitrile

To a stirred solution of 2-cyanoethanethioamide (500 mg, 5.00 mmol) in DMF (3 mL) was added drop wise a solution of 2-bromo-1-phenylethan-1-one (1 g, 5.00 mmol) in DMF (3 mL) at room temperature, and the reaction was stirred for another 50 min. The resulting solution was heated at 70° C. for 45 min, and the reaction was monitored by TLC. After the completion, the reaction mixture was diluted with EtOAc, washed with water, dried over anhydrous Na₂SO₄ and filtered. The filtrate obtained was concentrated under reduced pressure to get a crude residue which was purified by silica-gel column chromatography eluting with 0-7% ethyl acetate in n-hexane to afford 1 g of the desired compound. LCMS: [M+H]⁺=200.95. ¹H NMR (CDCl₃, 400 MHz): δ 7.88 (d, J=7.48 Hz, 2H), 7.48 (s, 1H), 7.41-7.47 (m, 2H), 7.37 (d, J=7.48 Hz, 1H), 4.18 (s, 2H).

Step 2: tert-butyl 2-amino-3-(benzo[d]thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of 2-(4-phenylthiazol-2-yl)acetonitrile (1 g, 5.00 mmol) in ethanol (10 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (1.19 g, 6.00 mmol), elemental sulphur (160 mg, 5.00 mmol) and morpholine (0.51 mL, 5.00 mmol) at room temperature. After the addition, the resulting mixture was heated to reflux at 85° C. for 2 h and monitored by TLC. The reaction mixture was evaporated under vacuum. After removal of solvent, the crude compound was purified by triturating with methanol to afford the title compound as a yellow solid (500 mg, yield 24%). LCMS: [M+H]⁺=414.02. ¹H NMR (DMSO-d₆, 400 MHz): 7.97 (d, J=7.59 Hz, 2H), 7.89 (s, 1H), 7.71 (s, 2H), 7.43-7.51 (m, 2H), 7.33-7.40 (m, 1H), 4.36 (m, 2H), 3.66 (t, J=5.13 Hz, 2H), 2.77-2.81 (m, 2H), 1.44 (s, 9H).

Step 3: tert-butyl 2-acetamido-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of tert-butyl 2-amino-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (500 mg, 1.21 mmol) in DCM (5 mL) at 0° C. was added DIPEA (0.42 mL, 2.42 mmol) and acetyl chloride (0.17 mL, 2.42 mmol). The reaction was by TLC, and after completion, the reaction mass was diluted with DCM and washed with saturated NaHCO₃ solution and brine. The combined organic layer was dried over Na₂SO₄, filtered and concentrated to get a crude residue (550 mg). This crude compound was purified by preparative HPLC to afford the title compound as a white solid (60 mg, 11% yield). LCMS: [M+H]⁺=456.0. ¹H NMR (CDCl₃, 400 MHz): δ 12.98 (br. s, 1H), 7.89 (d, J=7.34 Hz, 2H), 7.46-7.53 (m, 2H), 7.40-7.44 (m, 2H), 4.59 (m, 2H), 3.79 (t, J=5.38 Hz, 2H), 2.93-2.97 (m, 2H), 2.36 (s, 3H), 1.50 (s, 9H).

Step 4: N-(3-(4-phenylthiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (Compound 100)

To a solution of tert-butyl 2-acetamido-3-(4-phenylthiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (60 mg, 0.13 mmol) in dioxane (1 mL) at 0° C. was added 4M HCl in dioxane (1 mL). After the addition, the resulting mixture was stirred at room temperature for 2 h and the reaction was monitored by TLC. After completion, the reaction mixture was evaporated to dryness resulting in a crude residue which was purified by triturating with ether and pentane to afford the title compound as a pale yellow solid (50 mg HCl salt). LCMS: [M+H]⁺=355.95. ¹H NMR (DMSO-d₆, 400 MHz): 9.47 (br. s, 2H), 8.24 (s, 1H), 8.03 (d, J=7.34 Hz, 2H), 7.48-7.57 (m, 2H), 7.34-7.48 (m, 1H), 4.33 (s, 2H), 3.49 (t, J=5.87 Hz, 2H), 3.07-3.15 (m, 2H), 2.33 (s, 3H).

Example 2. Synthesis of 3-(Isopropylamino)-N-(3-(4-methylbenzo[d]oxazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 104)

Step 1: 2-(4-(Pyridin-2-yl)thiazol-2-yl)acetonitrile

2-Cyanoethanethioamide (400 mg, 3.99 mmol) was added to a solution of 2-bromo-1-(pyridin-2-yl)ethanone (1122 mg, 3.99 mmol) in DMF (8 mL) and the resulting mixture was stirred for 2 h at 70° C. The reaction mixture was cooled to RT, diluted with water and EtOAc, washed with brine (3×), dried over MgSO₄, filtered and concentrated. The residue was purified by SiO₂ chromatography (MeOH in DCM, 0 to 10% gradient) to afford the title compound (215 mg, 27%) as a brown solid.

Step 2: tert-Butyl 2-amino-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

A mixture of 2-(4-(pyridin-2-yl)thiazol-2-yl)acetonitrile (215 mg, 1.07 mmol), N-Boc-4-piperidone (213 mg, 1.07 mmol), sulfur (34 mg, 1.07 mmol), morpholine (0.093 mL, 1.07 mmol) in EtOH (4 mL) was stirred for 17 h at 90° C. The reaction mixture was cooled to RT, concentrated to half of its initial volume and the precipitated solid was collected by filtration. The solid was washed with EtOH and dried under vacuum to afford the title compound (200 mg, 45%) as a light green solid.

Step 3: tert-Butyl 2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

A mixture of tert-butyl 2-amino-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (100 mg, 0.241 mmol), 3-((tert-butoxycarbonyl)(isopropyl)amino)propanoic acid (84 mg, 0.362 mmol), T3P (50% in EtOAc, 0.287 mL, 0.482 mmol) and Et₃N (0.101 mL, 0.724 mmol) in EtOAc (2.4 mL) was stirred for 18 h at 65° C. The reaction mixture was cooled to RT, quenched with saturated NaHCO₃ and diluted with EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was taken in a minimum of EtOAc, sonicated and the precipitate was filtered off to afford the title compound (73 mg, 43%) as a light brown solid.

Step 4: 3-(Isopropylamino)-N-(3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 104)

A solution of HCl (4 N in dioxane, 1.0 mL) was added to a solution of tert-butyl 2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(pyridin-2-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (73 mg, 0.116 mmol) in DCM (2.0 mL) at RT. The resulting mixture was stirred for 2 h at RT and diluted with Et₂O (2.0 mL). The precipitated solid was collected by filtration, washed with Et₂O and lyophilized from water/MeCN to afford the title compound (36 mg, 61%) as a yellow solid. ¹H NMR (500 MHz): δ DMSO-d6, δ 12.06 (s, 1H), 9.71 (s, 2H), 9.23 (s, 2H), 9.04 (d, J=6.3 Hz, 2H), 8.97 (s, 1H), 8.44 (d, J=5.5 Hz, 2H), 4.34 (s, 2H), 3.47 (t, J=6.0 Hz, 2H), 3.34-3.27 (m, 1H), 3.25 (t, J=6.9 Hz, 2H), 3.12 (t, J=5.7 Hz, 2H), 3.04 (t, J=6.8 Hz, 2H), 1.29 (d, J=6.5 Hz, 6H). LC-MS: Calcd Mass [M+H]: 428.0; Found Mass [M+H]⁺: 428.2.

The following compounds were prepared using the same method outlined above for Compound 104:

Calcd. Found Compound Masss Mass No. ¹H NMR (500 MHz) [M + H] [M + H]⁺ 102 12.37 (s, 1H), 9.66 (s, 428.2 428.3 2H), 9.09 (s, 2H), 8.74 (d, 1H), 8.52 (s, 1H), 8.27-8.16 (m, 2H), 7.53 (t, 1H), 4.34 (s, 2H), 3.49 (s, 2H), 3.30 (d, J = 24.2 Hz, 3H), 3.23-3.11 (m, 4H), 1.28 (d, J = 6.1 Hz, 6H) 103 DMSO-d6 + D₂O, δ 428.2 428.2 9.34 (s, 1H), 8.77- 8.65 (m, 2H), 8.49 (s, 1H), 7.89-7.80 (m, 1H), 4.33 (s, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.32 (hept, J = 6.5 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.13 (t, J = 5.8 Hz, 2H), 3.07 (t, J = 6.9 Hz, 2H), 1.24 (d, J = 6.5 Hz, 6H). 5 NH missing due to D₂O 110 DMSO-d6 δ 12.39 (s, 444.2 444.2 1H), 9.64 (s, 2H), 9.08 (s, 2H), 8.79-8.67 (m, 1H), 8.49 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.12 (td, J = 7.7, 1.6 Hz, 1H), 7.53-7.46 (m, 1H), 4.34 (s, 2H), 3.66-3.61 (m, 2H), 3.48 (s, 4H), 3.32 (d, J = 1.8 Hz, 3H), 3.20- 3.12 (m, 4H).

Example 3. N-(3-(4-(3,6-Dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-3-(isopropylamino)propanamide (Compound 130)

Step 1: 3-((tert-Butoxycarbonyl)(isopropyl)amino)propanoic anhydride

DIC (856 mg, 6.8 mmol) added in one portion to a solution of 3-((tert-butoxycarbonyl)(isopropyl)amino)propanoic acid (3.13 g, 13.6 mmol) in DCM (14 mL) at 0° C. The resulting mixture was allowed to stir at room temperature for 1.5 h. The solvent was then evaporated and Et₂O added to the slurry and the white solid was then filtered off, rinsed with cold Et₂O. The filtrate was washed with a saturated solution of NaHCO₃, the combined organic layers were dried over anh. Na₂SO₄, filtered and concentrated to afford the title compound (2.63 g, 87%) as a colorless oil.

Step 2: tert-Butyl 2-(4-bromothiazol-2-yl)-2-cyanoacetate

tert-Butyl 2-cyanoacetate (18.6 g, 131.7 mmol) was added drop-wise to a solution of 2,4-dibromothiazole (20 g, 82.3 mmol) and grinded K₂CO₃ (34.1 g, 247.0 mmol) in dry NMP (101 mL) and the resulting mixture was stirred for 16 h at 85° C. The reaction mixture was cooled to RT and poured in water (900 mL). A solution of HCl 3N (250 mL) was added drop-wise until pH 2. The solid formed was filtered off, rinsed with water and hexanes and then air dried to afford the title compound (25 g, 100%) as a light brown solid.

Step 3: 2-(4-Bromothiazol-2-yl)acetonitrile

AcOH (101 mL, 1770 mmol) was added to a suspension of tert-butyl 2-(4-bromothiazol-2-yl)-2-cyanoacetate (25.0 g, 82.33 mmol) in a 4N HCl solution in water (103 mL, 411.6 mmol) and the resulting mixture was stirred at 80° C. for 15 min. The reaction mixture was cooled to RT, quenched with water and diluted with EtOAc. The layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO₄, filtered and co-evaporated 2 times with toluene. The residue was taken in a minimum of EtOAc and hexanes, sonicated and filtered off to afford the titled compound (6.38 g, 38%).

Step 4: tert-Butyl 2-amino-3-(4-bromothiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

A mixture of 2-(4-bromothiazol-2-yl)acetonitrile (5 g, 24.62 mmol), N-Boc-4-piperidone (4.9 g, 24.62 mmol), sulfur (790 mg, 24.62 mmol), morpholine (3.46 mL, 24.62 mmol), and Et₃N (2.15 mL, 24.62 mmol) in degassed EtOH (82 mL) was stirred for 2 h at 40° C. The reaction mixture was cooled to RT, concentrated and adsorbed on SiO₂. The residue was purified by SiO₂ chromatography (EtOAc in hexanes, 0 to 20% gradient) to afford the title compound (2.15 g, 21%) as a yellow solid.

Step 5: tert-Butyl 3-(4-bromothiazol-2-yl)-2-(3-((tert-butoxycarbonyl)(isopropyl)-amino)propan-amido)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

A mixture of tert-butyl 2-amino-3-(4-bromothiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate 2450 mg, 2.88 mmol), 3-((tert-butoxycarbonyl)(isopropyl)-amino)propanoic anhydride (3139 mg, 7.06 mmol), and DMAP (1797 mg, 14.7 mmol), in DCE (50 mL) was stirred for 16 h at RT. The reaction mixture was quenched with saturated NaHCO₃ and diluted with DCM. The layers were separated, the aqueous phase was extracted with DCM, and the combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by reverse phase chromatography (MeCN in a 10 nM NH₄HCO₂, 40 to 90% gradient) to afford the title compound (1640 mg, 43%) as a yellow solid.

Step 6: tert-Butyl 2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(3,6-dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate

A 20 mL pressure vessel was charged with tert-butyl 3-(4-bromothiazol-2-yl)-2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (1650 mg, 2.63 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1104 mg, 5.25 mmol), potassium tert-butanolate (884 mg, 7.88 mmol) and PCl₂(dppf)₂ (214.5 mg, 0.263 mmol). The vial was flushed with N2 and degassed Dioxane (18 mL) was added. The tube was sealed and heated at 120° C. under microwave irradiations for 60 min. The reaction was then filtrated over celite, washed with EtOAc, and concentrated. The residue was purified by flash chromatography (EtOAc in hexanes, 15% to 40% gradient) to afford the title compound (1118 mg, 67%).

Step 7: N-(3-(4-(3,6-Dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)-3-(isopropylamino)propanamide dihydrochloride (Compound 130)

A solution of HCl (4 N in dioxane, 10 mL) was added to a solution of tert-butyl 2-(3-((tert-butoxycarbonyl)(isopropyl)amino)propanamido)-3-(4-(3,6-dihydro-2H-pyran-4-yl)thiazol-2-yl)-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (2618 mg, 4.13 mmol) in DCM (20 mL) at RT. The resulting mixture was stirred for 2 h at RT and diluted with Et₂O (20 mL). The precipitated solid was collected by filtration, washed with Et₂O and lyophilized from water to afford the title compound (1900 mg, 91%) as a pale yellow solid. ¹H NMR (500 MHz): δ DMSO-d6, δ 12.84-12.13 (m, 1H), 9.54-9.10 (m, 2H), 8.77-8.51 (m, 2H), 7.86-7.59 (m, 1H), 6.89-6.57 (m, 1H), 4.37-4.29 (m, 4H), 3.91-3.84 (m, 2H), 3.55-3.44 (m, 2H), 3.28-3.23 (m, 3H), 3.12-3.00 (m, 4H), 2.58-2.53 (m, 2H), 1.29-1.21 (m, 6H). LC-MS: Calcd Mass [M+H]: 433.2; Found Mass [M+H]⁺: 433.3.

The following compounds were prepared using the same method outlined above for Compound 130:

Calcd. Found Compound Masss Mass No. ¹H NMR (500 MHz) [M + H] [M + H]⁺ 114 DMSO-d6 + D₂O, δ 431.2 431.1 8.20 (s, 1H), 7.95 (d, J = 0.5 Hz, 1H), 7.75 (s, 1H), 4.31 (s, 2H), 3.90 (s, 3H), 3.47 (t, J = 6.1 Hz, 2H), 3.33 (d, J = 6.5 Hz, 1H), 3.26 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 5.9 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 1.23 (d, J = 6.5 Hz, 6H). 5 NH missing due to D₂O 115 DMSO-d6, δ 11.95 (s, 446.1 446.2 1H), 9.65 (br s, 2H), 9.17 (t, J = 1.6 Hz, 1H), 8.82 (br s, 2H), 8.64 (d, J = 2.7 Hz, 1H), 8.54 (s, 1H), 8.37 (ddd, J = 10.1, 2.7, 1.8 Hz, 1H), 4.33 (s, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.34- 3.22 (m, 3H), 3.13 (t, J = 6.0 Hz, 2H), 3.09 (t, J = 7.0 Hz, 2H), 1.26 (d, J = 6.5 Hz, 6H). 116 DMSO-d6, δ 12.19 (s, 442.2 442.2 1H), 9.62 (br s, 2H), 9.22 (br s, 1H), 8.93 (br s, 2H), 8.57 (br s, 1H), 8.48 (br s, 1H), 7.71 (br s, 1H), 4.34 (s, 2H), 3.48 (t, J = 6.0 Hz, 2H), 3.36-3.31 (m, 1H), 3.27 (t, J = 7.0 Hz, 2H), 3.16- 3.10 (m, 4H), 2.64 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). 117 DMSO-d6, δ 11.47 (s, 431.2 431.1 1H), 9.74 (br s, 2H), 9.57 (br s, 1H), 9.12 (br s, 2H), 8.20 (s, 1H), 8.09 (s, 1H), 4.32 (s, 2H), 3.46 (t, J = 6.1 Hz, 2H), 3.35-3.27 (m, 1H), 3.22 (t, J = 6.9 Hz, 2H), 3.12 (dd, J= 17.8, 6.2 Hz, 4H), 2.36 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). 118 DMSO-d6, δ 12.25 (s, 408.1 408.1 1H), 11.36 (s, 1H), 9.48 (s, 1H), 8.89 (s, 2H), 7.60 (s, 1H), 4.31 (s, 2H), 3.46 (s, 2H), 3.38- 3.24 (m, 3H), 3.20 (t, J = 6.7 Hz, 2H), 3.06 (t, J = 5.8 Hz, 2H), 2.18 (s, 3H), 1.27 (d, J = 6.5 Hz, 6H). 119 DMSO-d6 + D₂O, δ 458.2 458.2 8.83 (s, 1H), 8.39- 8.30 (m, 2H), 8.03 (s, 1H), 4.31 (s, 2H), 3.93 (s, 3H), 3.48 (t, J = 5.9 Hz, 2H), 3.31 (hept, J = 6.6 Hz, 1H), 3.25 (t, J = 6.7 Hz, 2H), 3.13 (t, J = 6.4 Hz, 2H), 3.02 (t, J = 6.6 Hz, 2H), 1.22 (d, J = 6.5 Hz, 6H). 5 NH missing due to D₂O 120 DMSO-d6, δ 11.67 (s, 429.0/431.0 429.0/431.0 1H), 9.63 (s, 2H), 8.88 (s, 2H), 7.99 (s, 1H), 4.30 (br. s, 2H), 3.47- 3.39 (m, 2H), 3.28- 3.19 (m, 2H), 3.04- 2.97 (m, 4H), 1.26 (d, J = 6.5 Hz, 6H). 1H hidden under water signal 121 DMSO-d6, δ 11.94 (s, 442.2 442.3 1H), 9.59 (s, 2H), 8.92 (s, 2H), 8.64 (d, J = 4.4 Hz, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 7.76 (s, 1H), 4.27 (s, 2H), 3.23- 3.18 (m, 1H), 3.18- 3.11 (m, 4H), 3.06 (t, J = 5.4 Hz, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.80 (s, 3H), 1.18 (d, J = 6.5 Hz, 6H). 122 DMSO-d6, δ 12.07 (s, 442.2 442.1 1H), 9.57 (s, 2H), 9.14 (s, 1H), 8.84 (s, 2H), 8.60-8.40 (m, 3H), 4.27 (s, 2H), 3.44- 3.40 (m, 3H), 3.27- 3.23 (m, 2H), 3.22- 3.15 (m, J = 5.8 Hz, 3H), 3.13-3.01 (m, 4H), 1.20 (d, J = 6.5 Hz, 6H). 123 DMSO-d6, δ 12.02 (s, 442.2 442.3 1H), 9.06 (s, 1H), 8.65 (d, J = 5.5 Hz, 1H), 8.20 (s, 1H), 7.77 (d, J = 5.6 Hz, 1H), 4.33 (s, 2H), 3.48 (t, J = 6.1 Hz, 2H), 3.33-3.23 (m, 2H), 3.22 (t, J = 7.0 Hz, 3H), 3.12 (t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.8 Hz, 1H), 2.95 (t, J = 7.0 Hz, 2H), 2.67 (s, J = 6.8 Hz, 3H), 1.23 (d, 6H). 125 DMSO-d6, δ 12.55- 427.1 427.1 12.47 (m, 1 H), 9.56- 9.45 (m, 2 H), 8.88- 8.79 (m, 2 H), 8.31 (s, 1 H), 8.11-8.07 (m, 2 H), 7.63-7.59 (m, 2 H), 7.52-7.45 (m, 1 H), 4.42-4.36 (m, 2 H), 3.57-3.52 (m, 2 H), 3.35-3.27 (m, 3 H), 3.20-3.13 (m, 4 H), 1.34-1.28 (m, 6 H) 126 DMSO-d6, δ 12.40 (s, 432.2 432.4 1 H), 9.48 (br. s., 2 H), 9.21 (br. s., 2 H), 9.14 (br. s., 2 H), 7.85 (s, 1 H), 6.67 (br. s., 1 H), 4.33 (br. s., 2 H), 3.92 (br. s., 2 H), 3.48 (br. s., 2 H), 3.28-3.23 (m, 2 H), 3.17 (m, 6 H), 2.79 (br. s., 2 H), 2.37 (br. s., 1 H), 1.30-1.24 (m, 7 H) 127 DMSO-d6, δ 12.27 (s, 458.2 458.1 1H), 9.27 (br. s, 2H), 8.48 (dd, J = 7.5, 1.9 Hz, 1H), 8.46 (br. s, 2H), 8.29 (s, 1H), 8.27 (dd, J = 4.9, 1.9 Hz, 1H), 7.20 (dd, J = 7.5, 4.9 Hz, 1H), 4.36 (br. s, 2H), 4.07 (s, 3H), 3.51 (br. s, 2H), 3.35-3.23 (m, 2H), 3.12 (t, J = 5.8 Hz, 2H), 3.03 (t, J = 6.9 Hz, 2H), 1.24 (d, J = 6.5 Hz, 6H). 1H hidden under water signal 128 DMSO-d6, δ 11.99 (s, 429.2 429.0 1H), 9.50-9.41 (m, 4H), 9.25 (s, 1H), 8.63 (br. s, 2H), 8.58 (s, 1H), 4.35 (s, 2H), 3.48 (br. s, 2H), 3.35-3.24 (m, 2H), 3.13 (t, J = 5.7 Hz, 2H), 3.08 (t, J = 7.0 Hz, 2H), 1.25 (d, J = 6.5 Hz, 6H). 1H hidden under water signal 129 DMSO-d6, δ 12.40 (s, 444.1 444.1 1H), 12.12 (br. s, 1H), 9.62 (br. s, 2H), 9.05 (br. s, 2H), 8.64 (s, 1H), 8.37 (dd, J = 7.1, 2.0 Hz, 1H), 7.53 (d, J = 5.6 Hz, 1H), 6.62 (t, J = 6.7 Hz, 1H), 4.33 (s, 2H), 3.35-3.30 (m, 2H), 3.29-3.22 (m, 2H), 3.16 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 5.6 Hz, 2H), 1.28 (t, J = 6.8 Hz, 6H). 1H hidden under water signal

Example 4. Synthesis of 2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (Compound 101)

Step 1: Ethyl 2-(cyanomethyl)thiazole-4-carboxylate

To a solution of 2-cyanoethanethioamide 2 (1 g, 9.98 mmol) in THF (25 mL) was added ethyl 3-bromo-2-oxopropanoate 1 (1.25 mL, 9.98 mmol) at 0° C. The resulting reaction mixture was refluxed at 70° C. for 3 h, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by column chromatography to afford compound 3 as a yellow solid (0.86 g, yield 86%). LCMS: [M+1]⁺=196.96.

Step 2: Step 2: tert-butyl 2-amino-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of ethyl 2-(cyanomethyl)thiazole-4-carboxylate 3 (0.86 g, 4.38 mmol) in ethanol (20 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (0.874 g, 4.38 mmol) followed by morpholine (0.381 g, 4.38 mmol) and sulphur (0.14 g, 4.38 mmol), and the resulting mixture was heated to 80° C. for 3 h and monitored by TLC. After completion, the reaction mixture was evaporated to give a crude residue which was triturated with methanol to afford compound 4 as a yellow solid (1.3 g, yield 73.86%). LCMS: [M+Na]⁺=431.85.

Step 3: tert-butyl 2-acrylamido-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of tert-butyl 2-amino-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate 4 (1.1 g, 2.68 mmol) in DCM (15 mL) at 0° C. was added DIPEA (0.52 g, 4.03 mmol) followed by 3-chloropropanoyl chloride (0.51 g, 4.03 mmol) and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After completion, the reaction mass was diluted with 10% MeOH/DCM and washed with NaHCO₃ solution. The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated to afford the compound 5 as a yellow solid (1.4 g, crude). LCMS: [M+H]⁺=464.14.

Step 4: tert-butyl 3-(4-(ethoxycarbonyl)thiazol-2-yl)-2-(3-(isopropylamino)propanamido)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of tert-butyl 2-acrylamido-3-(4-(ethoxycarbonyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1.4 g, 3.02 mmol) in MeOH (20 mL), propan-2-amine (0.26 g, 4.53 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness under reduced pressure. The crude compound was purified by column chromatography to afford the compound 6 as a yellow solid (1.1 g, yield 70.06%). LCMS: [M+1]⁺=523.24.

Step 5: 2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid

To a stirred solution of compound 6 (0.5 g, 0.957 mmol) in THF: H₂O (1:1, 8 mL) mixture was added LiOH (0.046 g, 1.91 mmol) and the reaction was stirred at rt for 12 h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was acidified using dilute HCl up to pH 6 and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulphate and concentrated to afford the compound 7 as a yellow solid (0.3 g, yield 63.42%). LCMS: [M+1]⁺=495.36.

Step 6: 2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (Compound 101)

To a solution of 2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid 7 (0.1 g, 0.202 mmol) in dioxane (1 mL) at 0° C., 4M HCl in dioxane (2 mL) was added. After the addition, the resulting mixture was stirred at room temperature for 2 h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was evaporated in vacuum resulting in a crude residue which was purified by trituration with diethyl ether and pentane to afford the title compound as a yellow solid (0.06 g, yield 63.82%). LCMS: [M+1]⁺=394.80. ¹H NMR (400 MHz, DMSO-d6) δ 13.30 (br. s, 1H), 12.50 (s, 1H), 9.60 (s, 2H), 8.98 (s, 2H), 8.58 (s, 1H), 4.32 (s, 2H), 3.52 (t, J=5.1 Hz, 2H), 3.19-2.98 (m, 5H), 1.23-1.21 (m, 6H).

The following compounds were prepared using the same method outlined above for Compound 101:

Compound Mass No. ¹H NMR (400 MHz) [M + H]⁺ 105 DMSO-d₆: δ 12.07 (s, 1H), 9.54 (br. s, 2H), 435.9 8.75 (br. s, 2H), 8.52 (d, J = 7.83 Hz, 1H), 8.36 (s, 1H), 4.32 (br. s, 2H), 4.13 (dt, J = 6.60, 13.57 Hz, 1H), 3.45-3.50 (m, 2H), 3.28 (d, J = 6.36 Hz, 3H), 3.07 (d, J = 5.87 Hz, 4H), 1.24 (dd, J = 6.85, 9.29 Hz, 12H) 106 DMSO-d₆: δ 11.78 (s, 1H), 9.55 (br. s, 2H), 464.30 8.82 (br. s, 2H), 8.25 (s, 1H), 4.32 (br. s, 2H), 3.62-3.79 (m, 8H), 3.42-3.47 (m, 2H), 3.19-3.26 (m, 3H), 3.03-3.08 (m, 2H), 2.99 (t, J = 6.85 Hz, 2H), 1.26 (d, J = 6.36 Hz, 6H). 107 DMSO-d₆: δ 8.52 (s, 1H), 8.24 (s, 2H), 3.90 408.75 (s, 3H), 3.83-3.88 (m, 2H), 3.05-3.13 (m, 4H), 2.98 (td, J = 6.36, 12.72 Hz, 2H), 2.79 (br. s, 2H), 2.72 (t, J = 6.85 Hz, 2H), 1.05 (d, J = 6.36 Hz, 6H). 108 DMSO-d₆: δ 11.88 (s, 1H), 9.50 (br. s, 2H), 451.85 8.70-8.81 (m, 3H), 8.38 (s, 1H), 4.33 (br. s, 2H), 3.45-3.54 (m, 8H), 3.29 (s, 3H), 3.02-3.11 (m, 5H), 1.25 (d, J = 6.36 Hz, 6H). 109 (DMSO-d₆, 400 MHz): δ 11.96 (s, 1H), 9.53 422.25 (br. s, 2H), 8.84 (br. s, 2H), 8.20 (s, 1H), 4.32 (br. s, 2H), 3.43-3.48 (m, 2H), 3.16-3.26 (m, 5H), 3.06 (br. s, 6H), 2.99 (t, J = 7.09 Hz, 2H), 1.26 (d, J = 6.36 Hz, 6H). 111 DMSO-d₆: δ 11.74 (br. s, 2H), 9.59 (br. s, 477.25 2H), 9.02 (br. s, 2H), 8.31 (s, 1H), 4.32 (br. s, 2H), 3.41-3.54 (m, 4H), 3.15-3.29 (m, 7H), 2.99-3.09 (m, 5H), 2.78 (br. s, 3H), 1.28 (d, J = 6.36 Hz, 6H 112 DMSO-d₆: δ 11.88 (s, 1H), 9.58 (br. s, 2H), 462.15 8.91 (br. s, 2H), 8.15 (s, 1H), 4.32 (br. s, 2H), 3.57-3.68 (m, 4H), 3.41-3.47 (m, 2H), 3.30 (d, J = 6.36 Hz, 1H), 3.23 (d, J = 5.87 Hz, 2H), 3.03-3.09 (m, 2H), 2.99 (t, J = 7.09 Hz, 2H), 1.66 (d, J = 4.40 Hz, 2H), 1.50-1.61 (m, 4H), 1.26 (d, J = 6.36 Hz, 6H).

Example 5. Synthesis of 2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-N-phenylthiazole-4-carboxamide (Compound 113)

Step 1: tert-Butyl 2-(3-(isopropylamino)propanamido)-3-(4-(phenylcarbamoyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of 2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (200 mg, 0.404 mmol) in DMF (5 mL) at 0° C. was added triethyl amine (0.11 mL, 0.809 mmol), PyBOP (316 mg, 0.607 mmol) and aniline (38 mg, 0.404 mmol). After the addition, the resulting mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was washed with water and extracted with 10% methanol in DCM (thrice). The combined organic layer was dried over Na₂SO₄, filtered and concentrated to give crude compound. The crude compound was purified by preparative HPLC to afford the desired compound as a yellow solid (25 mg, 11% yield). LCMS: [M-Boc]⁺=470.45.

Step 2: 2-(2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-N-phenylthiazole-4-carboxamide (Compound 113)

To a solution of tert-butyl 2-(3-(isopropylamino)propanamido)-3-(4-(phenylcarbamoyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (25 mg, 0.043 mmol) in dioxane (3 mL) at 0° C. was added 4M HCl in dioxane (2 mL). After the addition, the resulting mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was evaporated to dryness resulting in a crude residue was purified by trituration in diethyl ether and pentane to afford the title compound as a yellow solid (20 mg HCl salt, 84% yield). LCMS: [M+H]⁺=470.25. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.03 (s, 1H), 10.56 (s, 1H), 9.58 (br. s, 2H), 8.77 (br. s, 2H), 8.55-8.60 (m, 1H), 7.88 (d, J=7.83 Hz, 2H), 7.39 (t, J=7.83 Hz, 2H), 7.15 (t, J=7.34 Hz, 1H), 4.34 (br. s, 2H), 3.46-3.51 (m, 1H), 3.23-3.31 (m, 4H), 3.12 (d, J=6.36 Hz, 4H), 1.20-1.26 (m, 6H).

Example 6. Synthesis of 2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-N-(pyridin-3-yl)thiazole-4-carboxamide

Step 1: tert-Butyl 2-(3-(isopropylamino)propanamido)-3-(4-(pyridin-3-ylcarbamoyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (1)

To a solution of 2-(6-(tert-butoxycarbonyl)-2-(3-(isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)thiazole-4-carboxylic acid (300 mg, 0.607 mmol) in DMF (15 mL) was added pyridin-3-amine (68 mg, 0.728 mmol), triethyl amine (0.42 mL, 3.036 mmol), and T3P (0.3 mL, 50% wt solution in ethyl acetate) at room temperature. After the addition, the resulting mixture was warmed to 40° C. and stirred for 2 h. After completion, the reaction mixture was concentrated to give crude compound. The crude compound was purified by preparative HPLC to afford the desired compound as yellow solid (50 mg, yield 14%). LCMS: [M+H]⁺=570.90, 570.85. ¹H NMR (CDCl₃, 400 MHz): δ 12.14 (br. s, 1H), 10.68 (br. s, 1H), 8.92 (br. s, 1H), 8.49 (d, J=7.34 Hz, 1H), 8.30-8.39 (m, 2H), 8.16 (br. s, 1H), 7.29-7.36 (m, 1H), 4.55 (br. s, 2H), 3.74-3.78 (m, 2H), 3.07-3.29 (m, 5H), 2.87-2.91 (m, 2H), 1.50 (s, 9H), 1.21 (d, J=5.38 Hz, 6H).

Step 2: 2-(2-(3-(Isopropylamino)propanamido)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)-N-(pyridin-3-yl)thiazole-4-carboxamide (Compound 124)

To a solution of tert-butyl 2-(3-(isopropylamino)propanamido)-3-(4-(pyridin-3-ylcarbamoyl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (30 mg, 0.052 mmol) in dioxane (1 mL) at 0° C. was added 4M HCl in dioxane (1 mL). After the addition, the resulting mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was evaporated to dryness and the resulting in a crude residue was triturated in ether and pentane and purified by preparative HPLC to afford the title compound as a yellow solid (20 mg HCl salt). LCMS: [M+H]⁺=470.90. ¹H NMR (DMSO-d₆, 400 MHz): δ 11.96 (s, 1H), 11.30 (br. s, 1H), 9.67 (br. s, 2H), 9.30 (br. s, 1H), 8.95 (br. s, 2H), 8.70-8.72 (m, 1H), 8.68 (d, J=8.80 Hz, 1H), 8.53 (d, J=4.40 Hz, 1H), 7.77 (d, J=4.40 Hz, 1H), 4.32 (br. s, 2H), 3.44-3.49 (m, 2H), 3.21-3.32 (m, 3H), 3.16 (d, J=6.36 Hz, 2H), 3.07-3.14 (m, 2H), 1.24 (d, J=6.36 Hz, 6H).

Example 7. Synthesis of (S)-3-(sec-butylamino)-N-(3-(4-(pyridin-3-yl)thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 131)

Step 1: 2-bromo-1-(pyridin-3-yl)ethan-1-one

To a solution of 1-(pyridin-3-yl)ethan-1-one (2 g, 16.52 mmol) in acetic acid (5 mL) at 0° C. was added HBr in acetic acid (28 mL) followed by dropwise addition of bromine (1 mL). The resulting reaction mixture was heated to 40° C. for 2 h and then at 75° C. for 2 h, and the reaction was monitored by TLC. After completion, the mixture was cooled and diluted with diethyl ether. The solid precipitated was filtered and washed with diethyl ether and acetone. The crude compound was purified by recrystallization in methanol and ether to afford the desired compound as a brown solid (2 g crude). LCMS: [M+H]⁺=199.89.

Step 2: 2-(4-(pyridin-3-yl)thiazol-2-yl)acetonitrile

To a solution of 2-bromo-1-(pyridin-3-yl)ethan-1-one 2 (500 mg, 2.50 mmol) in DMF (5 mL) was added 2-cyanoethanethioamide (250 mg, 2.50 mmol) at room temperature and stirred for 16 h, and the reaction was monitored by TLC. After completion, the mixture was evaporated to dryness and the residue obtained was washed with diethyl ether and pentane to afford the title compound as a brown solid (400 mg crude). LCMS: [M+H]⁺=201.95.

Step 3: tert-butyl 2-amino-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of 2-(4-(pyridin-3-yl)thiazol-2-yl)acetonitrile (150 mg, 1.243 mmol), elemental sulphur (40 mg, 1.243 mmol) and morpholine (108 mg, 1.243 mmol) in ethanol (5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (247 mg, 1.243 mmol) at room temperature and the resulting reaction mixture was heated to reflux at 85° C. for 12 h. The reaction was monitored by TLC and after completion, the mixture was evaporated to dryness to afford the desired compound as brown solid (150 mg crude). LCMS: [M+H]⁺=415.21.

Step 4: tert-butyl 2-acrylamido-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of tert-butyl 2-amino-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (150 mg, 0.362 mmol) in DCM (10 mL) at 0° C. was added DIPEA (0.1 mL, 0.724 mmol) followed by 3-chloropropanoyl chloride (55 mg, 0.434 mmol). The reaction mixture was stirred at room temperature for 12 h and monitored by TLC. After completion, the reaction mixture was diluted with DCM and washed with saturated NaHCO₃ solution and brine. The separated organic layer was dried over Na₂SO₄, filtered and concentrated in vacuum to afford the title compound as a brown solid (120 mg crude). LCMS: [M+H]⁺=469.25,

Step 5: tert-butyl (S)-2-(3-(sec-butylamino)propanamido)-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate

To a solution of tert-butyl 2-acrylamido-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (300 mg, 0.641 mmol) in MeOH: THF (1:1, 20 mL) was added (S)-butan-2-amine (56 mg, 0.769 mmol). The resulting reaction mixture was stirred at room temperature for 15 h, and the progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated to dryness under reduced pressure. The crude residue was dissolved in DCM and washed with water. The combined organic layers were dried with anhydrous Na₂SO₄, filtered and concentrated to get a crude residue. This crude compound was purified by silica gel column chromatography eluting with 0-5% methanol in DCM to afford desired compound as yellow solid (200 mg, yield 58%). LCMS: [M+H]⁺=542.38.

Step 6: (S)-3-(sec-butylamino)-N-(3-(4-(pyridin-3-yl)thiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)propanamide (Compound 131)

To a solution of tert-butyl (S)-2-(3-(sec-butylamino)propanamido)-3-(4-(pyridin-3-yl)thiazol-2-yl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (100 mg, 0.184 mmol) in dioxane (5 mL) at 0° C. was added 4M HCl in dioxane (5 mL). After the addition, the resulting mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was evaporated in vacuum resulting in a crude residue which was purified by triturating with methanol. The solid obtained was filtered and washed with diethyl ether and n-pentane to afford the title compound as a yellow solid (30 mg). LCMS: [M+H]⁺=441.80. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.05 (s, 1H), 9.66 (br. s, 2H), 9.34 (br. s, 1H), 8.89-9.07 (m, 2H), 8.72 (d, J=4.40 Hz, 2H), 8.54 (s, 1H), 7.90 (br. s, 1H), 4.26 (br. s, 2H), 3.38-3.42 (m, 2H), 3.03-3.27 (m, 7H), 1.70-1.79 (m, 1H), 1.41-1.53 (m, 1H), 1.18 (d, J=6.36 Hz, 3H), 0.85 (t, J=7.34 Hz, 3H).

Example 8. c-Myc/Max/Ebox DNA AlphaScreen Assay

Compounds of the invention were assayed for c-Myc/Max/EBox activity as described in the following protocol. Human his₆-c-Myc and his₆-Max were used with biotinylated DNA containing a single Ebox sequence (biotinGGAAGCAGACCACGTGGTCTGCTTCC (SEQ ID NO: 1)) purchased from MWG Operon. Free c-Myc was generated from his₆-c-Myc through thrombin cleavage of the his₆ tag (SEQ ID NO: 2). For 384-well plate assays, 10 μL of a 2× solution of free c-Myc (20 nM final), Ni²⁺ coated Acceptor Beads (25 μg/ml final), and biotinylated Ebox oligo (10 nM final) were added to 384-well plates with a Biotek EL406 liquid handler. 50 nL of compounds from stock plates were added by pin transfer using a Janus Workstation (PerkinElmer), allowing the compounds to interact with c-Myc prior to c-Myc binding with Max. In the current assay, DMSO was not allowed to exceed 2% v/v of the assay. 10 μl of 2× master mix containing streptavidin-coated donor beads (25 μg/ml final) and his₆-Max (5 nM) were added. AlphaScreen measurements were performed on an Envision plate reader (PerkinElmer) utilizing the manufacturer's protocol.

Both master mixes were made in room temperature assay buffer (50 mM HEPES, 150 mM NaCl, 0.2% w/v BSA, 0.02% w/v Tween20, 40 μg/ml glycogen, 500 μM DTT, pH 8.0, wherein both DTT and glycogen were added fresh). Alpha beads were added to respective master solutions. All subsequent steps were performed in low light conditions. Solution 1: 2× solution of components with final concentrations of c-Myc Ni-coated Acceptor Beads (25 μg/ml), and biotinylated Ebox oligo (10 nM). Solution 2: 2× solution of streptavidin-coated donor beads (25 μg/ml final) and his₆-Max 10 μL. Solution 1 was added to 384-well plate (AlphaPlate-384, PerkinElmer) with Biotek EL406 liquid handler and the plates were centrifuged very briefly. 50 nL of compounds from stock plates were added by pin transfer using a Janus Workstation. Solution 2 (10 μL) was added with the liquid handler. Plates were sealed with foil to block light exposure and prevent evaporation. Plates were very briefly centrifuged followed by 2 hour incubation. AlphaScreen measurements were performed on an Envision 2104 utilizing the manufacturer's protocol. Excitation was at 680 nm for donor bead release of singlet oxygen and emission was read with a bandpass filter from 520-620 nm. Glycogen: Roche Diagnostics #10901393001. Plate 1536: Perkin Elmer, 6004350. Plate 384: Perkin Elmer, 6005350. Nickel-His Alpha Beads: 6760619R. The data from this assay are summarized in Table 2 below (Myc/Max/DNA Activity), where “A” represents a calculated IC₅₀ of less than 500 nM; “B” represents a calculated IC₅₀ of between 500 nM and 5 μM; “C” represents a calculated IC₅₀ of between 5 μM and 10 μM; “D” represents a value of greater than 10 μM, and “NT” represents a compound for which an assay result was not obtained.

TABLE 2 Compound # Myc/Max/DNA Activity 100 D 101 B 102 A 103 A 104 A 105 C 106 D 107 NT 108 D 109 D 110 B 111 D 112 D 113 D 114 A 115 A 116 A 117 B 118 B 119 A 120 B 121 B 122 A 123 B 124 A 125 B 126 A 127 A 128 A 129 A 130 B 131 NT

EQUIVALENTS

In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims. 

What is claimed is:
 1. A compound of structural formula I

or a pharmaceutically acceptable salt thereof, wherein: Y is S; Z is N(R⁵); R¹ is optionally substituted heterocyclyl or optionally substituted heteroaryl; R² is —C(R^(2a))(R^(2b))(R^(2c)), wherein: R^(2a) is halogen, CN, C₁-C₄ alkyl, or C₁-C₄ heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; each of R^(2b) and R^(2c) is, independently, hydrogen, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)O(C₁-C₆ heteroalkyl), or C(O)N(R^(3a))(R^(3b)), wherein any alkyl or heteroalkyl portion of R^(2b) and R^(2c) is optionally and independently substituted; each R³ is, independently, hydrogen, —C₁-C₆ alkyl, or —C₁-C₆ heteroalkyl, wherein any alkyl or heteroalkyl is optionally substituted; or two R³ bound to a common nitrogen atom are optionally taken together with the nitrogen atom to which they are commonly bound to form a 4-11 member heterocyclyl or heteroaryl; each R⁴ is, independently, hydrogen, halogen, —CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, N(R³)(R³), C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)N(R³)(R³), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, or (C₁-C₆ heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R⁴ is optionally and independently substituted; R⁵ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, (C₁-C₆ heteroalkylene)-heteroaryl, CH₂C(O)OR⁸, CH₂C(O)N(R¹⁰)(R⁹), or CH₂CH₂N(R¹⁰)(R⁹), wherein: R⁸ is hydrogen, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, (C₀-C₃ alkylene)-carbocyclyl, or (C₀-C₃ alkylene)-heterocyclyl; R⁹ is hydrogen or C₁-C₄ alkyl; and R¹⁰ is hydrogen, C₁-C₄ alkyl, C₁-C₄ heteroalkyl, (C₀-C₄ alkylene)-carbocyclyl, (C₀-C₄ alkylene)-heterocyclyl, (C₀-C₄ alkylene)-aryl, (C₀-C₄ alkylene)-heteroaryl, (C₁-C₄ alkyl)-O—(C₁-C₄ alkyl), (C₁-C₄ alkyl)-N—(C₁-C₄ alkyl)₂, (C₁-C₄ alkyl)-NH—(C₁-C₄ alkyl), C(O)—(C₁-C₄ alkyl), or C(O)—O—(C₁-C₄ alkyl), or R¹⁰ and R⁹ are taken together with the nitrogen atom to which they are commonly bound to form a 4- to 11-membered heterocyclyl or heteroaryl; n is 1; m is 1; and p is 0, 1, 2, 3, 4, 5, or
 6. 2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R⁵ is hydrogen.
 3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R¹ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl.
 4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R² is —(CH₂)₂—NH—CH(CH₃)₂, —(CH₂)₂—NH—(CH₂)₂—OCH₃, or —(CH₂)₂—NH—CH(CH₃)—CH₂CH₃.
 5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R³ is hydrogen and p is
 0. 6. The compound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 7. A pharmaceutically acceptable composition comprising a compound of claim 1 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 8. The compound of claim 6, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 9. The pharmaceutically acceptable composition of claim 7, wherein, in the compound or the pharmaceutically acceptable salt thereof, R is hydrogen.
 10. The pharmaceutically acceptable composition of claim 7, wherein, in the compound or the pharmaceutically acceptable salt thereof, R¹ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 2-oxo-1,2-dihydropyridin-3-yl, 1,2,3,6-tetrahydropyridin-4-yl, pyrimidin-5-yl, 2-methoxypyridin-3-yl, 5-methoxypyridin-3-yl, pyridin-3-ylaminocarbonyl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl, 6-methylpyridin-3-yl, 4-methyl-1H-imidazol-1-yl, 1-methyl-1H-pyrazol-4-yl, 5-fluoropyridin-3-yl, phenylaminocarbonyl, piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, or morpholin-4-ylcarbonyl.
 11. The pharmaceutically acceptable composition of claim 7, wherein, in the compound or the pharmaceutically acceptable salt thereof, R² is —(CH₂)₂—NH—CH(CH₃)₂, —(CH₂)₂—NH—(CH₂)₂—OCH₃, or —(CH₂)₂—NH—CH(CH₃)—CH₂CH₃.
 12. The pharmaceutically acceptable composition of claim 7, wherein, in the compound or the pharmaceutically acceptable salt thereof, R³ is hydrogen and p is
 0. 13. The pharmaceutically acceptable composition of claim 7, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 14. The pharmaceutically acceptable composition of claim 7, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R is an unsubstituted heterocyclyl or heteroaryl; R^(2a) is halogen, CN, C₁-C₄ alkyl, or C₁-C₄ heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R^(2b) and R^(2c) is, independently, hydrogen, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)O(C₁-C₆ heteroalkyl), or C(O)N(R^(3a))(R^(3b)), wherein any alkyl or heteroalkyl portion of R^(2b) and R^(2c) is unsubstituted; each R³ is, independently, hydrogen, —C₁-C₆ alkyl, or —C₁-C₆ heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R⁴ is, independently, hydrogen, halogen, —CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, N(R³)(R³), C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)N(R³)(R³), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, or (C₁-C₆ heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R⁴ is unsubstituted.
 16. The pharmaceutically acceptable composition of claim 7, wherein, in the compound or the pharmaceutically acceptable salt thereof, R¹ is an unsubstituted heterocyclyl or heteroaryl; R^(2a) is halogen, CN, C₁-C₄ alkyl, or C₁-C₄ heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; each of R^(2b) and R^(2c) is, independently, hydrogen, halogen, —CN, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)O(C₁-C₆ heteroalkyl), or C(O)N(R^(3a))(R^(3b)), wherein any alkyl or heteroalkyl portion of R^(2b) and R^(2c) is unsubstituted; each R³ is, independently, hydrogen, —C₁-C₆ alkyl, or —C₁-C₆ heteroalkyl, wherein any alkyl or heteroalkyl is unsubstituted; and/or each R⁴ is, independently, hydrogen, halogen, —CN, C₁-C₈ alkyl, C₁-C₈ heteroalkyl, N(R³)(R³), C(O)(C₁-C₆ alkyl), C(O)(C₁-C₆ heteroalkyl), C(O)O(C₁-C₆ alkyl), C(O)N(R³)(R³), (C₀-C₆ alkylene)-carbocyclyl, (C₁-C₆ heteroalkylene)-carbocyclyl, (C₀-C₆ alkylene)-heterocyclyl, (C₁-C₆ heteroalkylene)-heterocyclyl, (C₀-C₆ alkylene)-aryl, (C₁-C₆ heteroalkylene)-aryl, (C₀-C₆ alkylene)-heteroaryl, or (C₁-C₆ heteroalkylene)-heteroaryl, wherein any alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl or heteroaryl portion of R⁴ is unsubstituted.
 17. The compound of claim 15, wherein, in the compound or the pharmaceutically acceptable salt thereof, R⁵ is hydrogen.
 18. The compound of claim 15, wherein, in the compound or the pharmaceutically acceptable salt thereof, R¹ is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or pyrimidin-5-yl.
 19. The compound of claim 15, wherein, in the compound or the pharmaceutically acceptable salt thereof, R² is —(CH₂)₂—NH—CH(CH₃)₂, —(CH₂)₂—NH—(CH₂)₂—OCH₃, or —(CH₂)₂—NH—CH(CH₃)—CH₂CH₃.
 20. The compound of claim 15, wherein, in the compound or the pharmaceutically acceptable salt thereof, R³ is hydrogen and p is
 0. 21. The pharmaceutically acceptable composition of claim 16, wherein, in the compound or the pharmaceutically acceptable salt thereof, R⁵ is hydrogen.
 22. The pharmaceutically acceptable composition of claim 16, wherein, in the compound or the pharmaceutically acceptable salt thereof, R¹is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3,6-dihydro-2H-pyran-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, or pyrimidin-5-yl.
 23. The pharmaceutically acceptable composition of claim 16, wherein, in the compound or the pharmaceutically acceptable salt thereof, R² is —(CH₂)₂—NH—CH(CH₃)₂, —(CH₂)₂—NH—(CH₂)₂—OCH₃, or —(CH₂)₂—NH—CH(CH₃)—CH₂CH₃.
 24. The pharmaceutically acceptable composition of claim 16, wherein, in the compound or the pharmaceutically acceptable salt thereof, R³ is hydrogen and p is
 0. 